title: Down-regulation of FXYD3 is induced by transforming growth factor-β signaling via ZEB1/δEF1 in human mammary epithelial cells.
abstract: FXYD3, a regulator of Na, K-ATPase, was identified as an mRNA overexpressed in murine breast cancers induced by neu oncogene, which had inactivated transforming growth factor (TGF)-β signaling due to the defect of TGF-β receptor I (TβRI) expression. To elucidate whether the expression of FXYD3 mRNA was regulated by TGF-β signaling, we used a normal human mammary epithelial cell line, MCF-10A which responds to TGF-β and tumor necrosis factor (TNF)-α, followed by induction of epithelial-to-mesenchymal transition (EMT). Here, we showed that FXYD3 at plasma membrane in epithelial state of MCF-10A cells was decreased by treatment of TGF-β and TNF-α. The repression of FXYD3 mRNA induced by TGF-β and TNF-α in MCF-10A cells was abolished by TβRI inhibitor or Smad3 inhibitor, but not by small interfering RNA (siRNA) for Smad2. In addition, expression level of FXYD3 mRNA was up-regulated by the silencing of ZEB1/δEF1 transcriptional repressor which was a down-stream target gene of TGF-β and an inducer of EMT. On the other hand, expression level and cellular localization of E-cadherin and N-cadherin were not changed by siRNA for FXYD3 in MCF-10A and human breast cancer MCF-7 cells. These results suggest that FXYD3 is a target gene of TGF-β signaling through ZEB1/δEF1, but is not directly involved in EMT.
authors.affiliation: Department of Molecular Physiology, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga 525–8577, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Mukaisho
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugihara
authors.forename: Takanori
authors.initials: T
authors.lastname: Hattori
authors.forename: Shinji
authors.initials: S
authors.lastname: Asano
mesh_terms: D001940:Breast / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: C091777:FXYD3 protein, human; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D051896:Smad Proteins, Receptor-Regulated; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I